• Author Q and A Series: Alcohol, the Microbiota, and Liver Disease

Author Q and A Series: Alcohol, the Microbiota, and Liver Disease

Chronic alcohol consumption disrupts the intestinal microbiota to reduce production of saturated long-chain fatty acids and subsequently the proportion and functions of hepatoprotective lactobacilliPeng Chen et al report in the January issue of Gastroenterology.

Dietary approaches to restore levels of saturated fatty acids in the intestine might therefore reduce ethanol-induced liver injury in patients with alcoholic liver disease.

We asked study’s senior author Bernd Schnabl some questions about the study—here are his answers:

 

Q: What gave you the idea that alterations to intestinal microbiota might be involved in alcoholic liver disease?

A: It was known for quite a while that chronic alcohol consumption is accompanied by changes in the intestinal microbiome. It was also known that alcoholic liver disease requires a leaky gut and translocation of bacterial products to the liver. However, we did not know exactly how alterations in the microbiome contribute to alcoholic liver disease. We therefore performed metagenomic sequencing of the gut microbiota in mice chronically fed alcohol.

Q: What were the main differences you found in the intestinal microbes, and their activities, between mice fed alcohol vs those that were not?

A: We found that after chronic alcohol feeding the capacity of intestinal bacteria to synthesize saturated fatty acids significantly decreased. We confirmed this by metagenomic and metabolomic analyses.

Q: Do humans and mice have similar alterations in the microbiota with alcohol consumption? 

A: We have shown in the past that mice fed alcohol show a decrease in many of the intestinal probiotic bacteria including Lactobacillus. This was recently confirmed in humans. Interestingly, after a short period of alcohol abstinence, intestinal lactobacilli populations recover.

Q: How does alcoholism affect the microbiota, and in turn, how does this affect the liver?

A: Chronic ethanol feeding reduces the capacity of intestinal bacteria to synthesize saturated long-chain fatty acids in mice. Feeding saturated long-chain fatty acids to these mice increased intestinal levels of probiotic lactobacilli. These bacteria appear to produce factors that stabilize the leaky gut. Less bacterial products, such as lipopolysaccharide (LPS), reach the liver. This prevents hepatic inflammation and liver disease.

Q: How do long-chain fatty acids protect the liver?

A: Lacobacillus seem to use saturated long-chain fatty acids in vivo and in vitro as an energy source for proliferation. Chronic ethanol intake might therefore decrease levels of Lactobacillus species by reducing intestinal levels of saturated fatty acids. Lactobacillus might protect against liver damage by directly stabilizing the mucosal barrier, but the exact mechanism of how lactobacilli do this, is currently not known.

Q: What other microbes and their activities or metabolites might be involved?

This is a very good question. We only know that dysbiosis disrupts the gut barrier facilitating bacterial translocation. However, we do not know which microbes, microbial products or metabolites are causing this onset of a leaky gut, which is an area of active research.

Q: How might this information be used to treat patients with alcoholic liver disease, or prevent its development?

A: Consumption of saturated fatty acids might protect alcoholics from a leaky gut syndrome. However, saturated fatty acid might increase the risk of cardiac disease in these patients and we cannot recommend this.

Q: What are the most important questions to answer next?

A: The most important question is to determine how dysbiosis causes the intestine to become leaky. In addition, it is important to determine how Lactobacillus stabilizes the gut barrier.

Q: How did you become interested in studying this subject?

A: Interactions between the gut and liver can promote liver disease. We compared changes in the microbiome associated with various liver diseases. What we found is that a dietary change, such as western diets or alcohol consumption, results in more dramatic changes of the gut microbiome compared to other liver diseases. We now would like to understand how dysbiosis contributes to these liver diseases.

 

In an editorial that accompanies the article, Herbert Tilg and Bin Gao describe the interactions between ethanol, diet, microbiota, and immunity in the gut that contribute to development of chronic alcoholic liver disease:

Ethanol down-regulates expression of bactericidal proteins Reg3b and Reg3g, resulting in dysbiosis and bacterial overgrowth. Ethanol also inhibits expression of bacterial genes (eg, FabD, FabF, and FabG) involved in the biosynthesis of long-chain fatty acids (LCFA), and subsequently decreases LCFA-dependent Lactobacilli—bacteria that restric gut permeability. Also, acetaldehyde directly damages gut epithelial integrity. All of these changes increase of bacteria-derived factors in the circulation and finally the liver, which promote liver inflammation and ALD.

Ethanol downregulates expression of bactericidal proteins Reg3b and Reg3g, resulting in dysbiosis and bacterial overgrowth. Ethanol also inhibits expression of bacterial genes (eg, FabD, FabF, and FabG) involved in the biosynthesis of long-chain fatty acids (LCFA), and subsequently decreases LCFA-dependent Lactobacilli—bacteria that restrict gut permeability. Also, acetaldehyde directly damages the gut to reduce epithelial integrity. All of these changes increase concentrations of bacteria-derived factors (such as LPS) in the circulation and liver to promote liver inflammation (via Toll-like receptors, TLRs) and alcoholic liver disease.

 

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